Project Summary Mu-opioid receptor (MOR) agonists (e.g., morphine) are highly efficacious for the treatment of pain. However, their therapeutic benefits are coupled with unwanted side effects like tolerance, respiratory depression, and addiction, indicating the need for improved therapeutic options. One pharmacological strategy for reducing side effects of opioid treatments is to design biased MOR agonists. Biased MOR agonists reduce certain side effects (e.g., respiratory depression) by preferentially activating distinct intracellular pathways of G protein- coupled receptors in a ligand-specific manner, thereby increasing their therapeutic selectivity. However, it is currently unknown if the therapeutic selectivity to produce antinociception over abuse liability is superior for biased MOR agonists relative to standard opioid treatments. This fellowship proposes to evaluate the therapeutic selectivity of biased MOR agonists across a spectrum of bias using molecular (i.e., intracellular signaling transduction assays) and behavioral (i.e., self-administration, antinociception) procedures. Specifically, Aim 1 will determine the degree of bias of the test ligands by calculating their potency to produce G-protein signaling over b-arrestin recruitment in CHO-K1 cells expressing the rat MOR. Aim 2 will evaluate the potency and efficacy of the test ligands to produce abuse-related effects in self-administration. Finally, Aim 3 will measure the potency and efficacy of the test ligands to produce antinociceptive effects across a range of pain modalities. Sex effects will also be investigated in Aims 2 and 3. As a final measure, we will calculate a ?therapeutic window? for each ligand as a ratio of the ligands? reinforcing/antinociceptive potencies, and these values will be correlated with the bias factors obtained in Aim 1 to determine if the degree of signaling bias is associated with therapeutic selectivity. Ultimately, the proposed research will provide key information regarding the utility of a new class of candidate opioid treatments with reduced side effects.